Background
Idiopathic pulmonary fibrosis (IPF), the most common fibrotic interstitial lung disease (ILD), is a chronic, progressive, and irreversible disease characterized by progressive extracellular matrix accumulation leading to respiratory insufficiency. The management strategies for IPF include relieving symptoms, maintaining patient quality of life and slowing disease progression. Apart from non-pharmacological treatments such as long-term oxygen therapy or rehabilitation, antifibrotics are the gold standard and should be started as soon as possible after the diagnosis of IPF [
1].
Pirfenidone (PFD), an oral pyridine with antifibrotic, anti-inflammatory and antioxidant functions, is currently approved for the treatment of IPF in most countries and recommended by the latest guidelines [
1,
2]. Evidence from the CAPACITY and ASCEND randomized controlled trials (RCTs) showed a significant reduction in the relative decline in forced vital capacity (FVC) over 72 weeks compared to the placebo group [
3,
4]. Furthermore, the pooled analysis and meta-analysis suggested a lower relative risk of death in PFD-treated patients than in placebo-treated patients [
5]. N-acetylcysteine (NAC), a tripeptide (g-glutamyl-cysteinyl glycine), can replenish glutathione storage levels, increase the antioxidant capacity and correct the imbalance of oxidants and antioxidants associated with fibroproliferation [
6]. On the basis of the negative results of the PANTHER trial [
7], NAC did not receive a positive recommendation as a treatment for IPF in the latest international guidelines [
1,
7].
A substantial number of IPF patients receive combined PFD and NAC therapy [
8‐
10]; however, data on the efficacy, safety, and tolerability of this combination are scarce. A recent placebo-controlled trial (PANORAMA) found that the rate of skin side effects was higher in the PFD + NAC group than in the PFD alone group [
11]. However, other studies, including a study with inhaled NAC, suggest a slower lung function decline and a similar side effect profile in patients undergoing PFD + NAC treatment compared with patients undergoing PFD alone [
8,
12‐
14].
Here, we systematically reviewed all studies with combined PFD and NAC treatment in IPF patients and performed a meta-analysis to compare the efficacy, safety, and tolerability of treatment with combined PFD and NAC vs treatment with PFD alone.
Method and materials
Literature search
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the PRISMA 2009-checklist. In addition, the meta-analysis was registered in PROSPERO (registration number: CRD42019134890).
A structured literature search was performed for studies on the safety and efficacy of combined PFD and NAC treatment in IPF patients. The following databases were searched from the earliest available dates to May 2019: PubMed, EMBASE, the Cochrane Library, Ovid, ProQuest, Web of Science and Chinese databases (including the China National Knowledge Infrastructure (CNKI), Chinese VIP Information (VIP), and the Wan Fang database). In addition, “
clinicaltrials.gov” and the bibliographies of previous meta-analyses on PFD or NAC were checked for relevant studies. The search terms included “idiopathic pulmonary fibrosis”, “IPF”, and “pulmonary fibrosis” for the disease and “pirfenidone”, “Esbriet”, and “acetylcysteine” for the intervention. No language or research type restriction was adopted.
Study selection
The inclusion criteria for the meta-analysis were as follows: (1) IPF patients diagnosed according to the 2011 American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines [
15]; (2) interventions referring to combined PFD and NAC treatment, regardless of whether administration was oral or inhaled; and (3) the control group consisted of patients who received PFD alone. All appropriate studies were included in the meta-analysis.
Two reviewers (HYS and DWY) inspected all studies after removing duplicate studies by reviewing titles and abstracts. Relevant studies were assessed by viewing the full-text articles to select studies that met the inclusion criteria mentioned above. Disagreements were resolved by a consensus-based discussion.
To collect data on combined PFD + NAC therapy published in observational or retrospective studies involving patients with combined PFD, NAC, and corticosteroid/proton pump inhibitor treatment, we contacted the corresponding authors and obtained the original data regarding PFD + NAC therapy from some studies and excluded those patients receiving glucocorticoids other than PFD + NAC. Other studies with a questionable combined therapy group, incomplete data or an inappropriate control group were excluded [
16,
17]. All patients included in the meta-analysis had not received glucocorticoids since the pirfenidone treatment began.
Data extraction and quality scoring
Two reviewers (HYS and XRL) extracted data from the included studies, including the following baseline characteristics: (1) first author, published year, study type, numbers of patients in the PFD + NAC group and PFD group; (2) changes in pulmonary function test (PFT) parameters such as changes in the predicted forced vital capacity (ΔFVC%) and changes in the predicted diffusion capacity for carbon monoxide (ΔDLco%); and (3) the number of side effects including skin reactions (photosensitivity and skin rash) and gastrointestinal reactions (anorexia, diarrhoea, and reduced appetite); the number of intolerable side effects leading to treatment discontinuation was also recorded.
The quality of the included observational studies was estimated using the Newcastle-Ottawa Quality Assessment Scale (NOS). Two reviewers (HYS and XRL) independently assessed the quality of the included studies in the following three domains: selection, comparability, and outcome. Each study score ranges from 0 to 9 stars in the NOS scoring system [
18]. The randomized controlled studies were assessed with the Cochrane Collaboration risk of bias assessment tool [
19].
Data analysis
The data extracted from the selected trials were used to generate forest plots in Stata SE 13.0 software (Stata Corp, College Station, TX, USA). The risk of patients experiencing side effects and other binary parameters are expressed as odds ratios (ORs) for both the included cohort and case-control studies. The changes in the PFT parameters and other continuous parameters are presented as standardized mean differences (SMDs) for different studies that adopted various PFT inclusion standards. We examined the level of heterogeneity to determine which type of analysis to use. If there was low heterogeneity (I
2 less than 40%), then we used a fixed effects model. If the I
2 statistic was greater than 40%, we applied a random effects model to summarize the data. Patients with the combination of PFD and inhaled NAC were only included in one case-control study [
11], and the sensitivity analysis excluding the case-control study and the secondary analysis with only oral administration studies were completed in one step. Two-tailed
p values less than 0.05 were considered significant.
Discussion
The present meta-analysis did not show superior efficacy of the combination PFD plus NAC therapy in slowing lung functional decline in IPF and showed comparable safety and tolerability compared to PFD alone.
The antifibrotic drug pirfenidone can significantly reduce lung functional decline in IPF patients; therefore, it is recommended in international guidelines as the treatment of choice [
1]. However, patients still present with gradually worsening symptoms and a constant loss of quality of life [
22], and the outcome is comparable to those of many malignant diseases [
23]. There is still an unmet need to halt disease progression. Antioxidative therapy with NAC is discussed as a potential additional therapy in some patients in clinical practice.
The randomized placebo-controlled trial IFIGENIA investigated NAC treatment vs the standard treatment with prednisone plus azathioprine in 182 mild to moderate IPF patients over 48 weeks [
24]. Combined therapy with high-dose NAC (1800 mg, d), prednisone and azathioprine significantly preserved the absolute vital capacity (VC) and DLco compared to the combination of prednisone and azathioprine [
24]. However, the results of the PANTHER-IPF trial [
25], which also enrolled patients with mild to moderate IPF, showed that there was no significant difference in the decline in FVC and showed a higher rate of serious adverse effects [
25] and especially a higher mortality rate in patients receiving triple therapy than in patients receiving the placebo. While another report of the PANTHER also demonstrated no benefit of NAC over the placebo [
7], a post hoc analysis of the PANTHER study [
26] suggested that the genotypic background of IPF patients may have an impact on the effects of NAC treatment. MUC5B and TOLLIP SNPs were retrospectively investigated in a subgroup of patients in the PANTHER trial. Patients with a rs3750920 (TOLLIP) TT genotype (25% of all patients) showed favourable outcomes regarding a reduction in the risk of the composite endpoint, defined as death, transplant, hospitalization or ≥ 10% FVC decline, while patients with a CC genotype had a non-significant increase in the composite physiological index (CPI) [
26].
Regarding lung function decline (especially FVC), our meta-analysis demonstrated comparable outcomes between the PFD + NAC group and PFD monotherapy group. Considering that the majority of studies included in this meta-analysis enrolled Caucasian patients with mild to moderate IPF (predicted FVC from 50 to 90%), the heterogeneity among these studies may be related to ethnicity because the studies by Ma and Sakamoto [
12,
14], which showed favourable efficacy results for the combination treatment, enrolled Asian patients. In addition, a speculative explanation for this phenomenon could be that the proportion of patients with the TOLLIP TT genotype in the treatment groups differed among the studies, but the data were not available [
7,
26]. Furthermore, direct antioxidant and anti-inflammatory effects on the alveoli by inhaled instead of oral NAC treatment may also contribute to the favourable outcomes in Sakamoto’s study [
14].
There are some considerations regarding the safety and tolerability of PFD and NAC treatment in IPF patients. Gastrointestinal (diarrhoea, anorexia, etc.) and skin side effects (photosensitivity and skin rash) are the most common adverse effects experienced by IPF patients receiving PFD treatment [
27,
28]. Compared to the findings from the PANORAMA trial, our meta-analysis showed a similar rate of side effects except for skin side effects (lower rate). The exact reason for this difference is unclear but may be related to differences in the patients’ habits, such as the time spent outdoors or the use of skin protection creams [
11].
Our meta-analysis has several limitations. First is the small number of included studies. Second, the meta-analysis included only one RCT, and the rest of the studies were observational studies and real-world experiences. Third, the lung function decline assessment was partial because scarce data were available for the 6MWD and blood gas analysis; therefore, we cannot exclude improvements in other outcome measures due to treatment with combined PFD + NAC. Fourth, the random effects model, which is generally used to analyse the overall effect when moderate heterogeneity exists (I2 > 40%), was applied for the analysis of patients experiencing at least one side effect and to assess differences in the FVC% decline between groups, leading to a wider confidence interval and a more conservative conclusion.
Conclusions
In conclusion, this systematic review and meta-analysis suggests that the combination of PFD and NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in the IPF study population. High-quality, multi-centre RCTs and large-sample real-world observational studies evaluating the safety, tolerability, and efficacy of PFD + NAC therapy vs PFD monotherapy and investigating the genetic background of patients are needed to validate these results.
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